Ongoing Projects

Local tissue priming through complement-mediated fibroblast activation as novel mechanism of progressive fibrosing interstitial lung disease

Recent data in arthritis, in which a relapsing-remitting disease course is a key feature, suggest that complement-mediated fibroblast activation with enhanced inflammasome activity sensitizes tissue for inflammation. Our own data showed that in different subtypes of fibrosing ILD, various pulmonary resident cells – and particularly inflammatory fibroblasts - expressed complement (-related) genes. Furthermore, lung-derived complement proteins in bronchoalveolar lavage fluid (BALF) and plasma of patients with fibrosing ILD significantly correlated with parameters of lung function and tissue injury and were reproducible in the acute model of bleomycin (BLM)-induced ILD, which suggests the suitability of this animal model to study injury-related changes in complement activation and their potential impact on disease development and perpetuation. Thus, we hypothesize that in ILD, tissue priming provides an explanation for the transition from self-limited to chronic inflammation and fibrosis and that pulmonary fibroblasts expressing high amounts of complement components are key effector cells within this process. We therefore aim to delineate the mechanisms of local tissue priming in chronic fibrosing ILD by using a combination of experimental models of resolving and persisting ILD. Specifically, we will evaluate a) whether repeated inflammatory challenges induce functional changes in lung fibroblasts in vivo (“priming”) and b) whether activation of lung fibroblasts with enhanced inflammasome activity is a complement-mediated process that can be abrogated by blocking complement signaling.

HRCT-derived radiomics features for classification of anti-fibrotic treatment responses in experimental and human fibrosing interstitial lung disease

­Fibrosing ILD is a chronic progressive diseases in which irreversible tissue remodelling impairs lung function. Treatment with the anti-fibrotic drug nintedanib slows lung function decline. However, efficacy is often difficult to judge in individual patients due to inherent disease variability and because it warrants 6-12 months of treatment. In this study, we explore if HRCT-derived radiomic signatures can serve as biomarkers of treatment response in (experimental) fibrosing ILD.

Novel Targeted Approach for the Visualisation of Inflammation using a novel 18F-AzaFol radiotracer for PET Imaging in Large Vessel Vasculitis

Giant cell arteritis (GCA) is a large vessel vasculitis (LVV), which affects 0.5-1% of individuals aged ≥ 50 years with high morbidity (constitutional symptoms, vision loss, limb ischemia) and mortality (stroke, dissection of aorta and its branching vessels). Activated macrophages expressing folate receptor- β (FR-β) play a prominent role in pulmonary and vascular inflammation including LVV. In LVV, targeting macrophages represents an efficient anti-inflammatory treatment strategy. In our multi-disciplinary study, we evaluate whether macrophage-targeted imaging and the integration of computationally derived imaging metadata (radiomics) and of molecular data may improve the (differential-) diagnosis of LVV from “vasculitis mimics” compared to available imaging (18F-FDG-PET) and serological routine markers.

Immune cellular therapy (ICT) platform for liquid and solid cancer types and systemic autoimmune diseases

Cellular therapies consisting of engineered immune cells have entered clinical practice. As ‘living drugs’ genetically engineered immune cell therapies (ICT) can identify and react to various disease conditions. This special ability opens up many avenues for future therapeutic applications. Many preclinical and clinical studies are ongoing with the intention to evaluate different strategies to modify immune cells not only for oncological indications but also for inflammatory and infectious diseases. Within this multidisciplinary project, we plan to establish an independent platform for ICT for liquid and solid cancer types as well as refractory systemic autoimmune diseases. This local platform will allow us to build alliances between bench and bedside consisting of basic/translational research, the establishment of a local GMP CAR T facility and clinical research. With the establishment of a center of excellence for ICT, we will be able to close the gap between patient and cell-product as well as cell-product and research. Our sub-project aims at the development of a CAR T cell eligibility tool for stratification of refractory patients with systemic autoimmune diseases for CAR T cell therapy. Immune phenotyping of peripheral blood mononuclear cells (PBMCs) and analysis of B-cell regulating and/or secreted serum cytokines will be performed to create a composite signature to identify responders to CD19 B cell targeted CAR T cell therapy.

Molecular and cellular characterization of ANCA-associated vasculitis

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are autoimmune diseases of small and medium-sized vessels, which can affect any organ. To date, therapeutic management of these patients is based on the clinical presentation and presence of subtypes of ANCA antibodies. However, a large number of patients develop irreversible complications, possibly because the current classifications on which treatment strategies are based do not consider potential molecular and cellular differences between similarly classified patients. The identification of matching molecular and cellular signatures as well as biomarkers for the prediction of treatment failure or relapse has great potential to advance our understanding of disease pathogenesis, thereby enabling the development of targeted and individualized therapies. A special focus lays on the research of neutrophils, which are key cells in the disease pathogenesis being at the same time victims and culprits by presenting antigens and attacking vessel walls.

Molecular patterns of immune cell activation in patients with arthritis

Joint inflammation (arthritis) is a hallmark of most rheumatic diseases, which substantially affects the patient’s body function and quality of life. There are more than 100 different entities manifesting arthritis, but they importantly differ in their etiology, their non-arthritic symptoms, severity, chronicity and long-term outcome. The most common forms of idiopathic arthritis are osteoarthritis (OA), rheumatoid arthritis (RA) and spondyloarthritis (SpA), including psoriatic arthritis (PsA). Despite the invention of new antirheumatic treatments 20-25% of RA patients do not respond to treatment and cannot achieve remission. Synovial tissue analysis is crucial in the differential diagnosis of monoarthritis as well as undifferentiated oligo- and polyarthritis. A unique cell activation pattern clearly distinguishes RA and PsA synovium from each other and from all other types of arthritis.

A currently undetermined number of subtypes of RA and PsA exists, which can better be defined by clustering of multi-omics data. Thus, our research focuses on synovial biopsies and joint aspirations for systematic analysis and comparison of the inflammatory nature and activated cell types in differently classified arthritides. Treating these patients according to their subtype could improve treatment response, quality of life and reduce the burden for healthy systems and patients equally.